Genetic Predisposition to Chronic Lymphocytic Leukemia Is Mediated by a BMF Super-Enhancer Polymorphism.
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ICR Authors
Authors
Kandaswamy, R
Sava, GP
Speedy, HE
Beà, S
Martín-Subero, JI
Studd, JB
Migliorini, G
Law, PJ
Puente, XS
Martín-García, D
Salaverria, I
Gutiérrez-Abril, J
López-Otín, C
Catovsky, D
Allan, JM
Campo, E
Houlston, RS
Sava, GP
Speedy, HE
Beà, S
Martín-Subero, JI
Studd, JB
Migliorini, G
Law, PJ
Puente, XS
Martín-García, D
Salaverria, I
Gutiérrez-Abril, J
López-Otín, C
Catovsky, D
Allan, JM
Campo, E
Houlston, RS
Document Type
Journal Article
Date
2016-08-23
Date Accepted
2016-07-20
Abstract
Chronic lymphocytic leukemia (CLL) is an adult B cell malignancy. Genome-wide association studies show that variation at 15q15.1 influences CLL risk. We deciphered the causal variant at 15q15.1 and the mechanism by which it influences tumorigenesis. We imputed all possible genotypes across the locus and then mapped highly associated SNPs to areas of chromatin accessibility, evolutionary conservation, and transcription factor binding. SNP rs539846 C>A, the most highly associated variant (p = 1.42 × 10(-13), odds ratio = 1.35), localizes to a super-enhancer defined by extensive histone H3 lysine 27 acetylation in intron 3 of B cell lymphoma 2 (BCL2)-modifying factor (BMF). The rs539846-A risk allele alters a conserved RELA-binding motif, disrupts RELA binding, and is associated with decreased BMF expression in CLL. These findings are consistent with rs539846 influencing CLL susceptibility through differential RELA binding, with direct modulation of BMF expression impacting on anti-apoptotic BCL2, a hallmark of oncogenic dependency in CLL.
Citation
Cell reports, 2016, 16 (8), pp. 2061 - 2067
Source Title
Publisher
CELL PRESS
ISSN
2211-1247
eISSN
2211-1247
Collections
Research Team
Cancer Genomics
Molecular & Population Genetics
Molecular & Population Genetics